RAD51C germline mutation carriers have a higher tendency to develop TOC and BC. However, the risk of breast cancer after a diagnosis of TOC in RAD51C mutation carriers remains unclear. The patient in the present study received niraparib maintenance treatment after first-line chemotherapy and survived for 3 years with no signs of TOC recurrence, and metachronous breast cancer was diagnosed at an early stage.

The c.838-2 A > G intronic variant results from an A to G substitution two nucleotides upstream of exon 6 in RAD51C [2, 9]. The mutation is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The mutation is classified as likely pathogenic in ClinVar. However, the actual pathogenicity of this mutation is unknown. Functional analysis of this mutation should be performed in the future. Individuals with RAD51C mutations have a higher risk of developing primary breast or ovarian cancer than non-carriers. Both TOC and BC risks for RAD51C pathogenic mutation carriers vary according to family history of cancer [4]. Carriers of a germline mutation in any of the RAD51 genes were more likely to have a family history of ovarian cancer, although the difference was not statistically significant [3]. However, no family history was found in the present patient.

Ovarian cancer is the most common cause of death among gynecological cancers. Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer, regardless of breast cancer timing [6]. Clinical trials have demonstrated promising response rates among ovarian cancer patients with BRCA1/2 germline mutations treated with PARP inhibitors. RAD51C and RAD51D mutations can also predict the response to PARPis, similar to BRCA1/2 mutations [5]. Our present observations are in agreement with these findings. In the present study, the patient tended to benefit from niraparib treatment. Studies have shown that mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness to germline BRCA1/2 mutations [10]. Overall, the exact prognostic role of RAD51C mutation should be determined in multicenter studies with larger sample sizes.

Interestingly, Kondrashova et al. found that analyses of primary and secondary mutations in RAD51C and RAD51D could provide evidence for these primary mutations conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance [11]. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and combination strategies. With the occurrence of breast cancer, whether the patient have developed resistance to PARPi was not sure since there were no signs of recurrence of ovarian cancer.

Emerging evidence has found that patients with BRCA-associated OC have a lower risk of developing subsequent primary or contralateral breast cancer than mutation carriers without OC [12]. For patients with BRCA-associated ovarian cancer, overall survival is dominated by OC deaths, and the risk of dying from OC is greater than the risk of developing BC. These results support nonsurgical management of BC risk in women with BRCA-OC [7]. Imaging surveillance should be advocated during the first several years after ovarian cancer diagnosis, after which the benefits of risk-reducing mastectomy (RRM) can be considered based on patient age and BRCA mutation status [13]. Some researchers have suggested that RRM or MRI screening should only be recommended for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer [14]. The planned screening and prevention strategies for breast cancer have not been determined for ovarian cancer patients with RAD51C mutations. Intensive breast screening was performed in the present patient but not for preventive mastectomy. It is worth noting that multi-omics analysis and liquid biopsy should be performed to identify the underlying mechanisms of metachronous breast cancer.

In the era of PARPi, PARPi can prevent breast cancer occurrence but also prolong the survival of patients with ovarian cancer and increase the possibility of breast cancer occurrence. The risk assessment and screening strategy for metachronous breast cancer in ovarian cancer patients with RAD51C mutations should be determined by incorporating many factors such as family history, mutation status, PARPi response, tumor stage, and survival. The age at diagnosis of ovarian cancer may be higher in patients with mutations in RAD51. Song et al. found that more RAD51 mutation carriers were diagnosed at ages 40–49 years than noncarriers, and no mutation carrier were diagnosed with ovarian cancer before the age of 40 years [3]. The age at diagnosis of ovarian cancer in the present case was 65 years. Since the age of onset of breast and ovarian cancer in RAD51C mutation carriers is older, intensive breast screening as well as oophorectomy should be implemented even after the age of 60 for RAD51C mutation carriers. Most breast cancers following ovarian cancer at an early stage are detected by mammography in BRCA1/2 mutation carriers [8]. Average 3.3 years of subsequent breast cancer are diagnosed after EOC in BRCA carriers. The interval between TOC and BC diagnosis was 3.5 years in the present case, which is in accordance with previous studies. our case, metachronous breast cancer occurred following primary ovarian cancer in a RAD51C mutation carrier during niraparib treatment. Given the rarity of RAD51C mutations, there are no established treatment guidelines for these cases, especially for those who received PARPi treatment. Patients should receive adjuvant chemotherapy according to the pathological findings of metachronous breast cancer. Based on the results of the OlympiAD and EMBRACA trials, the two PARP inhibitors, olaparib and talazoparib, are included as category 1 preferred options for recurrent or stage IV breast cancer with germline BRCA1/2 mutations [15]. Whether the patient in the present study could continue to receive niraparib or another PARPi treatment is not sure. Whether adjuvant chemotherapy, radiotherapy, and endocrine therapy could be combined with PARPi therapy, if required, has not been determined. The optimal treatment plan may need to be determined through multidisciplinary discussion.

To the best of our knowledge, the metachronous breast cancer in this case may be the first report of second primary cancer in a fallopian tube cancer patient harboring a RAD51C mutation during niraparib treatment. Further studies are needed to determine optimal treatment. As patients with TOC have a longer life expectancy in the era of PARPi, the risk of second primary cancer following TOC is worth our attention, especially for those with germline mutations in homologous recombination repair genes. It’s worth noting that breast cancer is a common disease in women with older age. The development of breast cancer in this patient may also be caused by other mechanisms. Loss of heterozygosity analysis of RAD51C in breast cancer should be performed to clarify the pathogenesis.

In conclusion, patients with RAD51C mutations tend to derive benefits from niraparib treatment. Primary breast cancer following primary fallopian tube cancer in RAD51C mutation carriers treated with niraparib is rare, and the optimal treatment plans for these patients need to be determined through multidisciplinary discussion.